Role of the nuclear envelope in the pathogenesis of age-related bone loss and osteoporosis.
Ontology highlight
ABSTRACT:
SUBMITTER: Vidal C
PROVIDER: S-EPMC3727739 | biostudies-other | 2012
REPOSITORIES: biostudies-other
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Project description:Skeletal muscle weakness is an important determinant of age-related declines in independence and quality of life but its causes remain unclear. Accelerated ageing syndromes such as Hutchinson-Gilford Progerin Syndrome, caused by mutations in genes encoding nuclear envelope proteins, have been extensively studied to aid our understanding of the normal biological ageing process. Like several other pathologies associated with genetic defects to nuclear envelope proteins including Emery-Dreifuss muscular dystrophy, Limb-Girdle muscular dystrophy and congenital muscular dystrophy, these disorders can lead to severe muscle dysfunction. Here, we first describe the structure and function of nuclear envelope proteins, and then review the mechanisms by which mutations in genes encoding nuclear envelope proteins induce premature ageing diseases and muscle pathologies. In doing so, we highlight the potential importance of such genes in processes leading to skeletal muscle weakness in old age.
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Project description:PurposeThe molecular mechanisms of age-related bone loss are unclear and without valid drugs yet. The aims of this study were to explore the molecular changes that occur in bone tissue during age-related bone loss, to further clarify the changes in function, and to predict potential therapeutic drugs.MethodsWe collected bone tissues from children, middle-aged individuals, and elderly people for protein sequencing and compared the three groups of proteins pairwise, and the differentially expressed proteins (DEPs) in each group were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). K-means cluster analysis was then used to screen out proteins that continuously increased/decreased with age. Canonical signaling pathways that were activated or inhibited in bone tissue along with increasing age were identified by Ingenuity Pathway Analysis (IPA). Prediction of potential drugs was performed using the Connectivity Map (CMap). Finally, DEPs from sequencing were verified by Western blot, and the drug treatment effect was verified by quantitative real-time PCR.ResultsThe GO and KEGG analyses show that the DEPs were associated with inflammation and bone formation with aging, and the IPA analysis shows that pathways such as IL-8 signaling and acute-phase response signaling were activated, while glycolysis I and EIF2 signaling were inhibited. A total of nine potential drugs were predicted, with rapamycin ranking the highest. In cellular experiments, rapamycin reduced the senescence phenotype produced by the H2O2-stimulated osteocyte-like cell MLO-Y4.ConclusionWith age, inflammatory pathways are activated in bone tissue, and signals that promote bone formation are inhibited. This study contributes to the understanding of the molecular changes that occur in bone tissue during age-related bone loss and provides evidence that rapamycin is a drug of potential clinical value for this disease. The therapeutic effects of the drug are to be further studied in animals.
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